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Identification
Name Sorafenib
Accession Number DB00398 (APRD01304, DB07438)
Type small molecule
Groups approved
Description

Sorafenib (rINN), marketed as Nexavar by Bayer, is a drug approved for the treatment of advanced renal cell carcinoma (primary kidney cancer). It has also received “Fast Track” designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary liver cancer), and has since performed well in Phase III trials.
Sorafenib is a small molecular inhibitor of Raf kinase, PDGF (platelet-derived growth factor), VEGF receptor 2 & 3 kinases and c Kit the receptor for Stem cell factor. A growing number of drugs target most of these pathways. The originality of Sorafenib lays in its simultaneous targeting of the Raf/Mek/Erk pathway.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Sorafenib tosylate
Salts Not Available
Brand names
Name Company
Nexavar
Brand mixtures Not Available
Categories
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Anticancer Agents
CAS number 284461-73-0
Weight Average: 464.825
Monoisotopic: 464.08630272
Chemical Formula C21H16ClF3N4O3
InChI Key InChIKey=MLDQJTXFUGDVEO-UHFFFAOYSA-N
InChI
InChI=1S/C21H16ClF3N4O3/c1-26-19(30)18-11-15(8-9-27-18)32-14-5-2-12(3-6-14)28-20(31)29-13-4-7-17(22)16(10-13)21(23,24)25/h2-11H,1H3,(H,26,30)(H2,28,29,31)
Plain Text
IUPAC Name
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide
SMILES
CNC(=O)C1=NC=CC(OC2=CC=C(NC(=O)NC3=CC(=C(Cl)C=C3)C(F)(F)F)C=C2)=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenols and Derivatives
  • Halobenzenes
  • Anisoles
  • Phenyl Esters
  • Anilines
Substructures
  • Phenols and Derivatives
  • Amino Ketones
  • Pyridines and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Ureas and Derivatives
  • Aryl Halides
  • Carboxylic Acids and Derivatives
  • Halobenzenes
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Carboxamides and Derivatives
  • Imines
  • Phenyl Esters
  • Anilines
Pharmacology
Indication For the treatment of patients with advanced renal cell carcinoma.
Pharmacodynamics Sorafenib is a multikinase inhibitor targeting several serine/threonine and receptor tyrosine kinases. It is commonly available as a tosylate salt. Sorafenib is a multikinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib inhibits tumor growth of the murine renal cell carcinoma, RENCA, and several other human tumor xenografts in athymic mice. A reduction in tumor angiogenesis occurs in some tumor xenograft models.
Mechanism of action Sorafenib interacts with multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-ß). Several of these kinases are thought to be involved in angiogenesis, thus sorafenib reduces blood flow to the tumor. Sorafenib is unique in targeting the Raf/Mek/Erk pathway. By inhibiting these kinases, genetic transcription involving cell proliferation and angiogenesis is inhibited.
Absorption The mean relative bioavailability is 38-49% for the tablet form, when compared to an oral solution. With a high-fat meal, bioavailability is reduced by 29% compared to administration in the fasted state.
Volume of distribution Not Available
Protein binding 99.5%
Metabolism Sorafenib is metabolized primarily in the liver, undergoing oxidative metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib accounts for approximately 70-85% of the circulating analytes in plasma at steady- state. Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro potency similar to that of sorafenib. This metabolite comprises approximately 9-16% of circulating analytes at steady-state.
Route of elimination Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces, and 19% of the dose excreted in urine as glucuronidated metabolites.
Half life 25-48 hours
Clearance Not Available
Toxicity The highest dose of sorafenib studied clinically is 800 mg twice daily. The adverse reactions observed at this dose were primarily diarrhea and dermatologic events. No information is available on symptoms of acute overdose in animals because of the saturation of absorption in oral acute toxicity studies conducted in animals.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Bayer healthcare pharmaceuticals inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Nexavar 200 mg tablet 66.61 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 7235576 2000-01-12 2020-01-12
Canada 2315715 2010-06-22 2018-12-22
Canada 2359510 2007-02-13 2020-01-12
Properties
State solid
Experimental Properties
Property Value Source
water solubility Practically insoluble (as tosylate salt) Not Available
logP 3.8 Not Available
Predicted Properties
Property Value Source
water solubility 1.71e-03 g/l ALOGPS
logP 4.12 ALOGPS
logP 4.34 ChemAxon
logS -5.4 ALOGPS
pKa (strongest acidic) 11.55 ChemAxon
pKa (strongest basic) 2.03 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 3 ChemAxon
hydrogen donor count 3 ChemAxon
polar surface area 92.35 ChemAxon
rotatable bond count 6 ChemAxon
refractivity 114.52 ChemAxon
polarizability 41.11 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
PubChem Compound 216239 Link_out
PubChem Substance 46505329 Link_out
ChemSpider 187440 Link_out
BindingDB 16673 Link_out
ChEBI 50924 Link_out
ChEMBL 50924 Link_out
Therapeutic Targets Database DAP000006 Link_out
PharmGKB PA7000 Link_out
HET BAX Link_out
Drugs.com http://www.drugs.com/cdi/sorafenib.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Sorafenib Link_out
ATC Codes
  • L01XE05
AHFS Codes
  • 92:00.00
PDB Entries Not Available
FDA label show (310 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Carboplatin Sorafenib may enhance the adverse/toxic effect of carboplatin. Concurrent use of sorafenib with carboplatin and placlitaxel in patients with squamous cell lung cancer is contraindicated. The use of this combination in other settings is not specifically contraindicated, but any such use should be approached with added caution.
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Tretinoin The strong CYP2C8 inhibitor, Sorafenib, may decrease the metabolism and clearance of oral Tretinoin. Consider alternate therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Sorafenib is initiated, discontinued to dose changed.
Food Interactions Not Available
Targets

1. B-Raf proto-oncogene serine/threonine-protein kinase

Pharmacological action: yes
Actions: inhibitor

Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron

Organism class: human
UniProt ID: P15056 Link_out
Gene: BRAF Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flaherty KT: Chemotherapy and targeted therapy combinations in advanced melanoma. Clin Cancer Res. 2006 Apr 1;12(7 Pt 2):2366s-2370s. Pubmed
  2. Haluska FG, Ibrahim N: Therapeutic targets in melanoma: map kinase pathway. Curr Oncol Rep. 2006 Sep;8(5):400-5. Pubmed
  3. Kim S, Yazici YD, Calzada G, Wang ZY, Younes MN, Jasser SA, El-Naggar AK, Myers JN: Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice. Mol Cancer Ther. 2007 Jun;6(6):1785-92. Pubmed
  4. Eisen T, Ahmad T, Flaherty KT, Gore M, Kaye S, Marais R, Gibbens I, Hackett S, James M, Schuchter LM, Nathanson KL, Xia C, Simantov R, Schwartz B, Poulin-Costello M, O’Dwyer PJ, Ratain MJ: Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J Cancer. 2006 Sep 4;95(5):581-6. Epub 2006 Aug 1. Pubmed
  5. Lu X, Tang X, Guo W, Ren T, Zhao H: Sorafenib induces growth inhibition and apoptosis of human chondrosarcoma cells by blocking the RAF/ERK/MEK pathway. J Surg Oncol. 2010 Sep 1. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. RAF proto-oncogene serine/threonine-protein kinase

Pharmacological action: yes
Actions: inhibitor

Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. Part of the Ras-dependent signaling pathway from receptors to the nucleus. Protects cells from apoptosis mediated by STK3

Organism class: human
UniProt ID: P04049 Link_out
Gene: RAF1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Adnane L, Trail PA, Taylor I, Wilhelm SM: Sorafenib (BAY 43-9006, Nexavar(®)), a Dual-Action Inhibitor That Targets RAF/MEK/ERK Pathway in Tumor Cells and Tyrosine Kinases VEGFR/PDGFR in Tumor Vasculature. Methods Enzymol. 2005;407:597-612. Pubmed
  2. Gollob JA, Wilhelm S, Carter C, Kelley SL: Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol. 2006 Aug;33(4):392-406. Pubmed
  3. Huether A, Hopfner M, Baradari V, Schuppan D, Scherubl H: Sorafenib alone or as combination therapy for growth control of cholangiocarcinoma. Biochem Pharmacol. 2007 May 1;73(9):1308-17. Epub 2007 Jan 5. Pubmed
  4. Cascone T, Gridelli C, Ciardiello F: Combined targeted therapies in non-small cell lung cancer: a winner strategy? Curr Opin Oncol. 2007 Mar;19(2):98-102. Pubmed
  5. Gridelli C, Maione P, Del Gaizo F, Colantuoni G, Guerriero C, Ferrara C, Nicolella D, Comunale D, De Vita A, Rossi A: Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer. Oncologist. 2007 Feb;12(2):191-200. Pubmed
  6. Lu X, Tang X, Guo W, Ren T, Zhao H: Sorafenib induces growth inhibition and apoptosis of human chondrosarcoma cells by blocking the RAF/ERK/MEK pathway. J Surg Oncol. 2010 Sep 1. Pubmed

3. Vascular endothelial growth factor receptor 2

Pharmacological action: yes
Actions: antagonist

Receptor for VEGF or VEGFC. Has a tyrosine-protein kinase activity. The VEGF-kinase ligand/receptor signaling system plays a key role in vascular development and regulation of vascular permeability

Organism class: human
UniProt ID: P35968 Link_out
Gene: KDR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Schoffski P, Dumez H, Clement P, Hoeben A, Prenen H, Wolter P, Joniau S, Roskams T, Van Poppel H: Emerging role of tyrosine kinase inhibitors in the treatment of advanced renal cell cancer: a review. Ann Oncol. 2006 Aug;17(8):1185-96. Epub 2006 Jan 17. Pubmed
  2. Veronese ML, Mosenkis A, Flaherty KT, Gallagher M, Stevenson JP, Townsend RR, O’Dwyer PJ: Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol. 2006 Mar 20;24(9):1363-9. Epub 2006 Jan 30. Pubmed
  3. Rini BI: Sorafenib. Expert Opin Pharmacother. 2006 Mar;7(4):453-61. Pubmed
  4. Adnane L, Trail PA, Taylor I, Wilhelm SM: Sorafenib (BAY 43-9006, Nexavar(®)), a Dual-Action Inhibitor That Targets RAF/MEK/ERK Pathway in Tumor Cells and Tyrosine Kinases VEGFR/PDGFR in Tumor Vasculature. Methods Enzymol. 2005;407:597-612. Pubmed
  5. Lacouture ME, Desai A, Soltani K, Petronic-Rosic V, Laumann AE, Ratain MJ, Stadler WM: Inflammation of actinic keratoses subsequent to therapy with sorafenib, a multitargeted tyrosine-kinase inhibitor. Clin Exp Dermatol. 2006 Nov;31(6):783-5. Epub 2006 Jul 4. Pubmed

4. Vascular endothelial growth factor receptor 3

Pharmacological action: yes
Actions: antagonist

Receptor for VEGFC. Has a tyrosine-protein kinase activity

Organism class: human
UniProt ID: P35916 Link_out
Gene: FLT4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lathia C, Lettieri J, Cihon F, Gallentine M, Radtke M, Sundaresan P: Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer Chemother Pharmacol. 2006 May;57(5):685-92. Epub 2005 Aug 25. Pubmed
  2. Adnane L, Trail PA, Taylor I, Wilhelm SM: Sorafenib (BAY 43-9006, Nexavar(®)), a Dual-Action Inhibitor That Targets RAF/MEK/ERK Pathway in Tumor Cells and Tyrosine Kinases VEGFR/PDGFR in Tumor Vasculature. Methods Enzymol. 2005;407:597-612. Pubmed
  3. Gridelli C, Maione P, Del Gaizo F, Colantuoni G, Guerriero C, Ferrara C, Nicolella D, Comunale D, De Vita A, Rossi A: Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer. Oncologist. 2007 Feb;12(2):191-200. Pubmed
  4. Strumberg D: Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. Drugs Today (Barc). 2005 Dec;41(12):773-84. Pubmed
  5. Reddy GK, Bukowski RM: Sorafenib: recent update on activity as a single agent and in combination with interferon-alpha2 in patients with advanced-stage renal cell carcinoma. Clin Genitourin Cancer. 2006 Mar;4(4):246-8. Pubmed

5. FL cytokine receptor

Pharmacological action: yes
Actions: antagonist

Receptor for the FL cytokine. Has a tyrosine-protein kinase activity

Organism class: human
UniProt ID: P36888 Link_out
Gene: FLT3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Auclair D, Miller D, Yatsula V, Pickett W, Carter C, Chang Y, Zhang X, Wilkie D, Burd A, Shi H, Rocks S, Gedrich R, Abriola L, Vasavada H, Lynch M, Dumas J, Trail PA, Wilhelm SM: Antitumor activity of sorafenib in FLT3-driven leukemic cells. Leukemia. 2007 Mar;21(3):439-45. Epub 2007 Jan 4. Pubmed
  2. Lierman E, Lahortiga I, Van Miegroet H, Mentens N, Marynen P, Cools J: The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. Haematologica. 2007 Jan;92(1):27-34. Pubmed

6. Beta platelet-derived growth factor receptor

Pharmacological action: yes
Actions: antagonist

Receptor that binds specifically to PDGFB and PDGFD and has a tyrosine-protein kinase activity. Phosphorylates Tyr residues at the C-terminus of PTPN11 creating a binding site for the SH2 domain of GRB2

Organism class: human
UniProt ID: P09619 Link_out
Gene: PDGFRB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Gollob JA: Sorafenib: scientific rationales for single-agent and combination therapy in clear-cell renal cell carcinoma. Clin Genitourin Cancer. 2005 Dec;4(3):167-74. Pubmed
  2. Guida T, Anaganti S, Provitera L, Gedrich R, Sullivan E, Wilhelm SM, Santoro M, Carlomagno F: Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants. Clin Cancer Res. 2007 Jun 1;13(11):3363-9. Pubmed
  3. Unnithan J, Rini BI: The role of targeted therapy in metastatic renal cell carcinoma. ScientificWorldJournal. 2007 Mar 2;7:800-7. Pubmed

7. Mast/stem cell growth factor receptor

Pharmacological action: yes
Actions: antagonist

This is the receptor for stem cell factor (mast cell growth factor). It has a tyrosine-protein kinase activity. Binding of the ligands leads to the autophosphorylation of KIT and its association with substrates such as phosphatidylinositol 3-kinase (Pi3K)

Organism class: human
UniProt ID: P10721 Link_out
Gene: KIT Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Guida T, Anaganti S, Provitera L, Gedrich R, Sullivan E, Wilhelm SM, Santoro M, Carlomagno F: Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants. Clin Cancer Res. 2007 Jun 1;13(11):3363-9. Pubmed
  2. Koch CA, Gimm O, Vortmeyer AO, Al-Ali HK, Lamesch P, Ott R, Kluge R, Bierbach U, Tannapfel A: Does the expression of c-kit (CD117) in neuroendocrine tumors represent a target for therapy? Ann N Y Acad Sci. 2006 Aug;1073:517-26. Pubmed
  3. Lierman E, Lahortiga I, Van Miegroet H, Mentens N, Marynen P, Cools J: The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. Haematologica. 2007 Jan;92(1):27-34. Pubmed
  4. Cascone T, Gridelli C, Ciardiello F: Combined targeted therapies in non-small cell lung cancer: a winner strategy? Curr Opin Oncol. 2007 Mar;19(2):98-102. Pubmed
  5. Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C: Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006 Dec 15;66(24):11851-8. Pubmed
Enzymes

1. Cytochrome P450 2C9

Actions: inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O’Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Feb 25. Pubmed

2. Cytochrome P450 3A5

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

3. Cytochrome P450 3A7

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P24462 Link_out
Gene: CYP3A7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

4. Cytochrome P450 3A4

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Gomo C, Coriat R, Faivre L, Mir O, Ropert S, Billemont B, Dauphin A, Tod M, Goldwasser F, Blanchet B: Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma. Invest New Drugs. 2010 Aug 13. Pubmed
  3. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed
  4. Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O’Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Feb 25. Pubmed

5. UDP-glucuronosyltransferase 1-9

Actions: substrate

UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols

UniProt ID: O60656 Link_out
Gene: UGT1A9 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Gomo C, Coriat R, Faivre L, Mir O, Ropert S, Billemont B, Dauphin A, Tod M, Goldwasser F, Blanchet B: Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma. Invest New Drugs. 2010 Aug 13. Pubmed
  2. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed
  3. Keating GM, Santoro A: Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs. 2009;69(2):223-40. doi: 10.2165/00003495-200969020-00006. Pubmed

6. Cytochrome P450 2B6

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20813 Link_out
Gene: CYP2B6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O’Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Feb 25. Pubmed

7. Cytochrome P450 2C8

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O’Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Feb 25. Pubmed

8. Cytochrome P450 1A2

Actions: inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O’Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Feb 25. Pubmed

9. Cytochrome P450 2C19

Actions: inhibitor

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O’Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Feb 25. Pubmed

10. Cytochrome P450 2D6

Actions: inhibitor

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O’Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Feb 25. Pubmed
Transporters

1. Multidrug resistance-associated protein 4

Actions: inhibitor

May be an organic anion pump relevant to cellular detoxification

UniProt ID: O15439 Link_out
Gene: ABCC4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD: Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9. Epub 2009 Sep 22. Pubmed

2. Multidrug resistance protein 1

Actions: substrate, inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD: Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9. Epub 2009 Sep 22. Pubmed
  2. Lagas JS, van Waterschoot RA, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH: Breast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation. Mol Cancer Ther. 2010 Feb;9(2):319-26. Epub 2010 Jan 26. Pubmed

3. Canalicular multispecific organic anion transporter 1

Actions: inhibitor

Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter

UniProt ID: Q92887 Link_out
Gene: ABCC2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD: Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9. Epub 2009 Sep 22. Pubmed

4. ATP-binding cassette sub-family G member 2

Actions: substrate, inhibitor

Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. May be involved in brain-to-blood efflux. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. When overexpressed, the transfected cells become resistant to mitoxantrone, daunorubicin and doxorubicin, display diminished intracellular accumulation of daunorubicin, and manifest an ATP- dependent increase in the efflux of rhodamine 123

UniProt ID: Q9UNQ0 Link_out
Gene: ABCG2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD: Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9. Epub 2009 Sep 22. Pubmed
  2. Lagas JS, van Waterschoot RA, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH: Breast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation. Mol Cancer Ther. 2010 Feb;9(2):319-26. Epub 2010 Jan 26. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19